Modulation and analysis of cerebral perfusion in epilepsy and other neurological disorders

ABSTRACT

A system including an implantable neurostimulator device capable of modulating cerebral blood flow to treat epilepsy and other neurological disorders. In one embodiment, the system is capable of modulating cerebral blood flow (also referred to as cerebral perfusion) in response to measurements and other observed conditions. Perfusion may be increased or decreased by systems and methods according to the invention as clinically required.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. Ser. No. 11/104,628,filed Dec. 15, 2004, which is incorporated by reference herein.

BACKGROUND OF THE INVENTIONS

1. Field of the Inventions

The invention relates to medical devices for treating epilepsy, and moreparticularly to a system incorporating an implantable device capable ofcausing changes in cerebral blood flow.

2. Description of the Related Art

Epilepsy, a neurological disorder characterized by the occurrence ofseizures (specifically episodic impairment or loss of consciousness,abnormal motor phenomena, psychic or sensory disturbances, or theperturbation of the autonomic nervous system), is debilitating to agreat number of people. It is believed that as many as two to fourmillion Americans may suffer from various forms of epilepsy. Researchhas found that its prevalence may be even greater worldwide,particularly in less economically developed nations, suggesting that theworldwide figure for epilepsy sufferers may be in excess of one hundredmillion.

Because epilepsy is characterized by seizures, its sufferers arefrequently limited in the kinds of activities they may participate in.Epilepsy can prevent people from driving, working, or otherwiseparticipating in much of what society has to offer. Some epilepsysufferers have serious seizures so frequently that they are effectivelyincapacitated.

Furthermore, epilepsy is often progressive and can be associated withdegenerative disorders and conditions. Over time, epileptic seizuresoften become more frequent and more serious, and in particularly severecases, are likely to lead to deterioration of other brain functions(including cognitive function) as well as physical impairments.

The current state of the art in treating neurological disorders,particularly epilepsy, typically involves drug therapy and surgery. Thefirst approach is usually drug therapy.

A number of drugs are approved and available for treating epilepsy, suchas sodium valproate, phenobarbital primidone, ethosuximide, gabapentin,phenytoin, and carbamazepine, as well as a number of others.Unfortunately, those drugs typically have serious side effects,especially toxicity, and it is extremely important in most cases tomaintain a precise therapeutic serum level to avoid breakthroughseizures (if the dosage is too low) or toxic effects (if the dosage istoo high). The need for patient discipline is high, especially when apatient's drug regimen causes unpleasant side effects the patient maywish to avoid.

Moreover, while many patients respond well to drug therapy alone, asignificant number (at least 20-30%) do not. For those patients, surgeryis presently the best-established and most viable alternative course oftreatment.

Currently practiced surgical approaches include radical surgicalresection such as hemispherectomy, corticectomy, lobectomy and partiallobectomy, and less-radical lesionectomy, transection, and stereotacticablation. Besides being less than fully successful, these surgicalapproaches generally have a high risk of complications, and can oftenresult in damage to eloquent (i.e., functionally important) brainregions and the consequent long-term impairment of various cognitive andother neurological functions. Furthermore, for a variety of reasons,such surgical treatments are contraindicated in a substantial number ofpatients. And unfortunately, even after radical brain surgery, manyepilepsy patients are still not seizure-free.

Electrical stimulation is an emerging therapy for treating epilepsy.However, currently approved and available electrical stimulation devicesdo not perform any detection of neural activity and apply electricalstimulation to neural tissue surrounding or near implanted electrodessomewhat indiscriminately; they are not responsive to relevantneurological conditions. Responsive stimulation, in which neurologicalactivity is detected and electrical stimulation treatment is appliedselectively, is in clinical trials at the time of this writing.

The NeuroCybernetic Prosthesis (NCP) from Cyberonics, for example,applies continuous electrical stimulation to the patient's vagus nerve.This approach has been found to reduce seizures by about 50°< > in about50% of patients. Unfortunately, a much greater reduction in theincidence of seizures is needed to provide substantial clinical benefit.

The Activa device from Medtronic is a pectorally implanted continuousdeep brain stimulator intended primarily to treat Parkinson's disease.In operation, it continuously supplies an intermittent electrical pulsestream to a selected deep brain structure where an electrode has beenimplanted. Continuous stimulation of deep brain structures for thetreatment of epilepsy has not met with consistent success. To beeffective in terminating seizures, it is believed that one effectivesite where stimulation should be performed is near the focus of theepileptogenic region. The focus is often in the neocortex, wherecontinuous stimulation above a certain level may cause significantneurological deficit with clinical symptoms including loss of speech,sensory disorders, or involuntary motion. Accordingly, and to improvetherapeutic efficacy over indiscriminate continuous stimulation,research has been directed toward automatic responsive epilepsytreatment based on a detection of imminent seizure.

A typical epilepsy patient experiences episodic attacks or seizures.Those events, neurological states, and epileptiform activity evident onthe EEG shall be referred to herein as “ictal”.

Most prior work on the detection and responsive treatment of seizuresvia electrical stimulation has focused on analysis ofelectroencephalogram (EEG) and electrocorticogram (ECoG) waveforms. Incommon usage, the term “EEG” is used to refer to signals representingaggregate neuronal activity potentials detectable via electrodes appliedto a patient's scalp, though the term can also refer to signals obtainedfrom deep in the patient's brain via depth electrodes and the like.Specifically, “ECoGs” refer to signals obtained from internal electrodesnear the cortex of the brain (generally on or under the dura mater), butis often used to refer to direct brain signals from deeper structures aswell; an ECoG is a particular type of EEG. Unless the context clearlyand expressly indicates otherwise, the term “EEG” shall be usedgenerically herein to refer to both EEG and ECoG signals, regardless ofwhere in the patient's brain the electrodes are located.

It is generally preferable to be able to detect and treat a seizure ator near its beginning, or even before it begins. The beginning of aseizure is referred to herein as an “onset.” However, it is important tonote that there are two general varieties of seizure onsets. A “clinicalonset” represents the beginning of a seizure as manifested throughobservable clinical symptoms, such as involuntary muscle movements orneurophysiological effects such as lack of responsiveness. An“electrographic onset” refers to the beginning of detectableelectrographic activity indicative of a seizure. An electrographic onsetwill frequently occur before the corresponding clinical onset, enablingintervention before the patient suffers symptoms, but that is not alwaysthe case. In addition, there are changes in the EEG that occur secondsor even minutes before the electrographic onset that can be identified,and may be used to facilitate intervention before clear electrographicor clinical onsets occur. This capability would be considered seizureanticipation, in contrast to the detection of a seizure or its onset.Seizure anticipation is much like weather prediction there is anindication the likelihood has increased that a seizure will occur, butwhen exactly it will occur, or even if it will occur is not certain.

U.S. Pat. No. 6,018,682 to Rise describes an implantable seizure warningsystem that implements a form of the Gotman system. See, e.g., J.Gotman, Automatic seizure detection: improvements and evaluation,Electroencephalogr. Clin. Neurophysiol. 1990; 76(4): 317-24. However,the system described therein uses only a single detection modality,namely a count of sharp spike and wave patterns within a time period,and is intended to provide a warning of impending seizure activity inspite of a lack of evidence that spike and wave activity beingsufficiently anticipatory of seizures. This is accomplished withrelatively complex processing, including averaging over time andquantifying sharpness by way of a second derivative of the signal. TheRise patent does not disclose how the signals are processed at a lowlevel, nor does it explain detection criteria in any specific level ofdetail.

U.S. Pat. No. 6,016,449 to Fischell, et al. (which is herebyincorporated by reference as though set forth in full herein), describesan implantable seizure detection and treatment system. In the Fischellsystem, various detection methods are possible, all of which essentiallyrely upon the analysis (either in the time domain or the frequencydomain) of processed EEG signals. Fischell's controller is preferablyimplanted intracranially, but other approaches are also possible,including the use of an external controller. The processing anddetection techniques applied in Fischell are generally well suited forimplantable use. When a seizure is detected, the Fischell system appliesresponsive electrical stimulation to terminate the seizure, a capabilitythat will be discussed in further detail below.

All of these approaches provide useful information, and in some casesmay provide sufficient information for accurate detection and oranticipation of most imminent epileptic seizures.

It has been found that many clinical neurological disorders areassociated with abnormal blood flow patterns in the brain. These includeepilepsy, movement disorders, and psychiatric disorders. It wouldtherefore be advantageous to employ a system or method to monitor suchabnormal blood flow patterns, either in isolation or in connection withabnormal electrographic activity, to identify the status of the diseasestate and to monitor the short-term and or long-term progression of thedisease state with the intention of correcting the abnormal blood flowpatterns to provide clinical benefit. Such monitoring is preferablyaccomplished within the therapy delivery device (often aneurostimulator) to automatically adjust therapy delivery to the patientto more optimally bring about beneficial changes in brain blood flowpatterns either acutely or more long term. Therapy delivery may bedirect brain electrical stimulation, spinal cord stimulation, brain stemor peripheral nerve stimulation, or may be magnetic stimulation,somatosensory stimulation, or drug delivery. However, monitoring mayinclude means not included in the therapy delivery device, with therapybeing adjusted by a clinician. Monitoring of the brain blood flow can beaccomplished by the periodic application of non-invasive imagingtechniques including SPECT, PET, SISCOM, infrared, ultrasound, orimpedance techniques.

As is well known, it has been suggested that it is possible to treat andterminate seizures by applying electrical stimulation to the brain. See,e.g., U.S. Pat. No. 6,016,449 to Fischell et al., and H. R. Wagner, etal., Suppression of cortical epileptiform activity by generalized andlocalized ECoG desynchronization, Electroencephalogr. Clin.Neurophysiol. 1975; 39(5): 499-506. It has further been found thatelectrical stimulation can modulate blood flow in the brain. Corticalstimulation increases blood flow within hundreds of milliseconds at thesite of stimulation (T. Matsuura et al., “Hemodynamics evoked bymicroelectrical direct stimulation in rat somatosensory cortex,” Comp.Biochem. Physiol. A. Mol. Integr. Physiol. 1999 September; 124(1):47-52; see also S. Bahar et al. “THE RELATIONSHIP BETWEEN CEREBRAL.BLOOD VOLUME AND OXYGENATION FOLLOWING BIPOLAR STIMULATION OF THE HUMANCORTEX: EVIDENCE FOR AN INITIAL DIP.” AES 12-2004 New Orleans PosterSession). Stimulation of other brain structures or through the use oftranscranial magnetic stimulation can produce patterns of blood flowchanges including increases or reductions of blood flow) in targetedareas.

At the current time, there is no known implantable device that iscapable of treating abnormal neurological conditions, includingseizures, by changing cerebral perfusion either acutely or chronically.Furthermore, there is no known implantable device that is capable ofdetecting and or anticipating seizures or other neurological eventsbased on cerebral perfusion conditions and changes therein, alone or incombination with other observed conditions. As anticipated herein,modulation of blood perfusion in the brain may be employed for acute orchronic treatment of neurological conditions.

SUMMARY OF THE INVENTION

A system according to the invention includes an apparatus, preferablyimplantable, capable of modulating cerebral blood flow and/or sensingchanges in cerebral blood flow, either globally or locally, andresponding thereto to achieve acute and/or chronic changes in cerebralblood flow.

The invention provides for the use of electrical stimulation and oiliermodalities of stimulation (including transcranial magnetic stimulation)directed at a variety of anatomical targets to produce changes incortical blood flow to treat neurological disorders, including but notlimited to epilepsy. Stimulation may be applied “open loop” (on ascheduled basis), or “closed loop” as a result of information fromsensors, particularly blood flow, electrographic, or movement sensors.Therapy may also be provided on command by a physician, the patient, ora caregiver. Systems according to the invention may be adapted forimplantable use, or may be partially or completely external to thepatient.

Electrical stimulation may be applied directly to the cortex, oralternatively to deeper brain structures, or to the brain stem, spinalcord or to cranial or peripheral nerves. Electrical stimulation, when itis applied, may be pulsatile in nature or of an arbitrary waveformincluding sine-waves. Different stimulation patterns, and the locationof the stimulation may be varied depending upon the brain state. Forexample, a hypo-perfused seizure onset focus in the interictal state mayreceive a stimulation pattern specifically designed to maximize bloodflow. As the brain transitions into a pre-seizure state as determined bycharacteristic changes in blood flow, electrographic evidence, or evenby the patient feeling symptoms and communicating the information to thetherapy device, the stimulation pattern may be beneficially changed toenhance blood flow in neural pathways (for instance in those pathwaysemanating from the seizure focus), or to decrease excitability at theseizure focus for example by stimulation of the caudate.

One system according to the invention includes an implanted controlmodule, controllable via external equipment, that is capable of applyingtherapeutic intervention to alter cerebral blood flow via electrical,thermal, chemical, electromagnetic, or other therapy modalities setforth herein and described in greater detail below. Preferably, suchstimulation is not provided continuously, but intermittently, and meansare provided to verify the need and/or effects of blood flow stimulationaccording to the invention. For example, an external programmer may beused to command the implanted device to deliver stimulation, after whichmeasurements are taken (via imaging techniques or other methodsdescribed herein, including automatic measurements taken by theimplanted device) to verify the effects or progress of the therapy.Depending on the effects observed, the implanted device is programmed bythe external programmer with a preferred therapy regimen.

In an embodiment of the invention, automatic measurements are taken bythe implanted device via impedance plethysmography techniques. Thesemeasurements are recorded and later transferred to the externalprogrammer via wireless telemetry, and may be used by a clinician totailor therapy to the specific patient being treated.

A specific embodiment of a system according to the invention performsregular perfusion measurements and applies therapy automatically inresponse thereto. This embodiment includes an implanted control module,implanted electrodes on a seizure focus and on the caudate nucleus, andan implanted pulse oximetry perfusion sensor in the vicinity of theseizure focus. In addition, a perfusion sensor (with electrodes) may beimplanted on the contralateral lobe from the seizure focus. Afterimplant, baseline perfusion and electrographic data may be collected forat least several days and for several seizures while the patientrecovers from surgery. Commanded stimulation studies may be performed toassess the effect of different stimulation parameters at the seizurefocus and at the caudate on perfusion behavior. Stimulation at theseizure focus will generally increase perfusion (the seizure focus isgenerally hypo-perfused in the interictal period) whereas stimulation ofbrain stem structures or the caudate may decrease perfusion.

The implanted control module monitors perfusion at the epileptogenicfocus, taking pulsed measurements every 30 seconds to save power. Ifsudden changes in perfusion are detected, the sampling rate may beincreased for improved resolution. The control module runs a therapyalgorithm to slowly increase the perfusion level at the epileptogenicfocus to a target range by applying stimulation as programmed within apreset range of allowed parameters (pulse amplitude, pulse width, numberof pulses in a burst, pulse to pulse interval, interval between bursts,rate of change allowed from burst to burst). If the perfusion level atthe site of the seizure focus increases above the target range, thealgorithm calls for the control module to stimulate other brainstructures such as the caudate in an attempt to bring the perfusionlevel down to a target range (this target range may be different thanthe target used when stimulating the focus directly). The patient or acaregiver may be alerted if a trend towards increased perfusion of theepileptogenic focus occurs despite caudate stimulation. This would allowthe use of an increased dose of antiseizure medication only when abreakthrough seizure is likely to occur.

It should be noted that epilepsy, and other neurological disorderstreatable by a system according to the invention, vary greatly insymptomology and treatment strategies from patient to patient. Forexample, to give one example, although perfusion has generally beenobserved to be pathologically low and increase prior to an epilepticseizure, the reverse may be true in some patients or in some anatomicallocations. Accordingly, the present invention as described in detailherein provides a framework for the diagnosis and treatment ofneurological dysfunctions by sensing and responding to changes incerebral blood flow, but specific treatment strategies should bedetermined, customized, and altered as clinical observations andexperience dictate.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features, and advantages of the invention willbecome apparent from the detailed description below and the accompanyingdrawings, in which:

FIG. 1 is a schematic illustration of a patient's head showing theplacement of an implantable neurostimulator according to an embodimentof the invention;

FIG. 2 is a schematic illustration of a patient's cranium showing theimplantable neurostimulator of FIG. 1 as implanted, including leadsextending to the patient's brain;

FIG. 3 is a block diagram illustrating a system context in which animplantable neurostimulator according to the invention is implanted andoperated;

FIG. 4 is a block diagram illustrating the major functional subsystemsof an implantable cerebral blood flow modulation device according to theinvention;

FIG. 5 is a block diagram illustrating the major functional subsystemsof an implantable responsive blood flow modulation device according tothe invention;

FIG. 6 is a block diagram illustrating the functional components of thedetection subsystem of the implantable device shown in FIG. 4;

FIG. 7 is a block diagram illustrating the functional components of thetherapy subsystem of the implantable device shown in FIG. 4;

FIG. 8 is a schematic cutaway diagram of an optical sensing andstimulation probe according to the invention;

FIG. 9 is a schematic cutaway diagram of a thermographic sensing andstimulation probe according to the invention;

FIG. 10 is a schematic cutaway diagram of an ultrasonic sensing andstimulation probe according to the invention;

FIG. 11 is a schematic cutaway diagram of an electromagnetic sensing andstimulation probe according to the invention;

FIG. 12 is a schematic cutaway diagram of an electrochemical sensingprobe according to the invention;

FIG. 13 is a schematic cutaway diagram of an electrical sensing andstimulation lead according to the invention;

FIG. 14 is an exemplary graph of cerebral blood flow measurements inrelation to thresholds calculated according to the invention; and

FIG. 15 is a flow chart illustrating an exemplary sequence of stepsperformed in measuring cerebral blood flow and responding to treatepilepsy and other disorders according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below, with reference to detailedillustrative embodiments. It will be apparent that a system according tothe invention may be embodied in a wide variety of forms. Consequently,the specific structural and functional details disclosed herein arerepresentative and do not limit the scope of the invention.

FIG. 1 depicts an intracranially implanted neurostimulator device 110according to the invention, which in one embodiment is a smallself-contained responsive neurostimulator located under the patient'sscalp 112. As the term is used herein, a responsive neurostimulator is adevice capable of detecting or anticipating ictal activity (or otherneurological events) and providing electrical stimulation to neuraltissue in response to that activity, where the electrical stimulation isspecifically intended to terminate the ictal activity, treat aneurological event, prevent an unwanted neurological event fromoccurring, or lessen the severity or frequency of certain symptoms of aneurological disorder. As disclosed herein, the responsiveneurostimulator detects ictal activity by systems and methods accordingto the invention.

Preferably, an implantable device according to the invention is capableof detecting or anticipating any kind of neurological event that has arepresentative electrographic signature. While the disclosed embodimentis described primarily as responsive to epileptic seizures, it should berecognized that it is also possible to respond to other types ofneurological disorders, such as movement disorders (e.g. the tremorscharacterizing Parkinson's disease), migraine headaches, chronic pain,and neuropsychiatric disorders such as schizophrenia,obsessive-compulsive disorders, and depression. Preferably, neurologicalevents representing any or all of these afflictions can be detected whenthey are actually occurring, in an onset stage, or as a anticipatoryprecursor before clinical symptoms begin.

In the disclosed embodiment, the neurostimulator is implantedintracranially in a patient's parietal bone 210, in a location anteriorto the lambdoid suture 212 (see FIG. 2). It should be noted, however,that the placement described and illustrated herein is merely exemplary,and other locations and configurations are also possible, in the craniumor elsewhere, depending on the size and shape of the device andindividual patient needs, among other factors. The device 110 ispreferably configured to fit the contours of the patient's cranium 214.In an alternative embodiment, the device 110 is implanted under thepatient's scalp 112 but external to the cranium: it is expected,however, that this configuration would generally cause an undesirableprotrusion in the patient's scalp where the device is located. In yetanother alternative embodiment, when it is not possible to implant thedevice intracranially, it may be implanted pectorally (not shown), withleads extending through the patient's neck and between the patient'scranium and scalp, as necessary.

It should be recognized that the embodiment of the device 110 describedand illustrated herein is preferably a responsive neurostimulator fordetecting and treating epilepsy by detecting seizures or their onsets orprecursors, preventing and/or terminating such epileptic seizures, andresponding to clusters of therapies as described herein.

In an alternative embodiment of the invention, the device 110 is not aresponsive neurostimulator, but is an apparatus capable of detectingneurological conditions and events and performing actions in responsethereto. The actions performed by such an embodiment of the device 110need not be therapeutic, but may involve data recording or transmission,providing warnings to the patient, or any of a number of knownalternative actions. Such a device will typically act as a diagnosticdevice when interfaced with external equipment, as will be discussed infurther detail below.

The device 110, as implanted intracranially, is illustrated in greaterdetail in FIG. 2. The device 110 is affixed in the patient's cranium 214by way of a ferrule 216. The ferrule 216 is a structural member adaptedto fit into a cranial opening, attach to the cranium 214, and retain thedevice 110.

To implant the device 110, a craniotomy is performed in the parietalbone 210 anterior to the lambdoidal suture 212 to define an opening 218slightly larger than the device 110. The ferrule 216 is inserted intothe opening 218 and affixed to the cranium 214, ensuring a tight andsecure fit. The device 110 is then inserted into and affixed to theferrule 216.

As shown in FIG. 2, the device 110 includes a lead connector 220 adaptedto receive one or more electrical leads, such as a first lead 222. Thelead connector 220 acts to physically secure the lead 222 to the device110, and facilitates electrical connection between a conductor in thelead 222 coupling an electrode to circuitry within the device 110. Thelead connector 220 accomplishes this in a substantially fluid-tightenvironment with biocompatible materials.

The lead 222, as illustrated, and other leads for use in a system ormethod according to the invention, is a flexible elongated member havingone or more conductors. As shown, the lead 222 is coupled to the device110 via the lead connector 220, and is generally situated on the outersurface of the cranium 214 (and under the patient's scalp 112),extending between the device 110 and a burr hole 224 or other cranialopening, where the lead 222 enters the cranium 214 and is coupled to adepth electrode (e.g., one of the outputs 412-418 of FIG. 4, in anembodiment in which the outputs are implemented as depth electrodes)implanted in a desired location in the patient's brain. If the length ofthe lead 222 is substantially greater than the distance between thedevice 110 and the burr hole 224, any excess may be urged into a coilconfiguration under the scalp 112. As described in U.S. Pat. No.6,006,124 to Fischell et al., which is hereby incorporated by referenceas though set forth fully herein, the burr hole] 224 is sealed afterimplantation to prevent further movement of the lead 222; in anembodiment of the invention, a burr hole cover apparatus is affixed tothe cranium 214 at least partially within the burr hole 224 to providethis functionality.

The device 110 includes a durable outer housing 226 fabricated from abiocompatible material. Titanium, which is light, extremely strong, andbiocompatible, is used in analogous devices, such as cardiac pacemakers,and would serve advantageously in this context. As the device 110 isself-contained, the housing 226 encloses a battery and any electroniccircuitry necessary or desirable to provide the functionality describedherein, as well as any other features. As will be described in furtherdetail below, a telemetry coil may be provided outside of the housing226 (and potentially integrated with the lead connector 220) tofacilitate communications between the device 110 and external devices.Other portions of a system according to the invention may also bepositioned outside of the housing 226, as will be described in furtherdetail below.

The neurostimulator configuration described herein and illustrated inFIG. 2 provides several advantages over alternative designs. First, theself-contained nature of the neurostimulator substantially decreases theneed for access to the device 110, allowing the patient to participatein normal life activities. Its small size and intracranial placementcauses a minimum of cosmetic disfigurement. The device 110 will fit inan opening in the patient's cranium, under the patient's scalp, withlittle noticeable protrusion or bulge. The ferrule 216 used forimplantation allows the craniotomy to be performed and fit verifiedwithout the possibility of breaking the device 110, and also providesprotection against the device 110 being pushed into the brain underexternal pressure or impact. A further advantage is that the ferrule 216receives any cranial bone growth, so at explant, the device 110 can bereplaced without removing any bone screws—only the fasteners retainingthe device 110 in the ferrule 216 need be manipulated.

As stated above, and as illustrated in FIG. 3, a neurostimulatoraccording to the invention operates in conjunction with externalequipment. The implantable neurostimulator device 110 is mostlyautonomous (particularly when performing its usual sensing, detection,and stimulation capabilities), but preferably includes a selectablepart-time wireless link 310 to external equipment such as a programmer312. In the disclosed embodiment of the invention, the wireless link 310is established by moving a wand (or other apparatus) havingcommunication capabilities and coupled to the programmer 312 intocommunication range of the implantable neurostimulator device 110. Theprogrammer 312 can then be used to manually control the operation of thedevice, as well as to transmit information to or receive informationfrom the implantable neurostimulator 110. Several specific capabilitiesand operations performed by the programmer 312 in conjunction with thedevice will be described in further detail below.

The programmer 312 is capable of performing a number of advantageousoperations in connection with the invention. In particular, theprogrammer 312 is able to specify and set variable parameters in theimplantable neurostimulator device 110 to adapt the function of thedevice to meet the patient's needs, upload or receive data (includingbut not limited to stored EEG waveforms, parameters, or logs of actionstaken) from the implantable neurostimulator device 110 to the programmer312, download or transmit program code and other information from theprogrammer 312 to the implantable neurostimulator 310, or command theimplantable neurostimulator 110 to perform specific actions or changemodes as desired by a physician operating the programmer 312. Tofacilitate these functions, the programmer 312 is adapted to receiveclinician input 314 and provide clinician output 316: data istransmitted between the programmer 312 and the implantableneurostimulator device 110 over the wireless link 310.

The programmer 312 may be used at a location remote from the implantableneurostimulator 110 if the wireless link 310 is enabled to transmit dataover long distances. For example, the wireless link 310 may beestablished by a short-distance first link between the implantableneurostimulator device 110 and a transceiver, with the transceiverenabled to relay communications over long distances to a remoteprogrammer 312, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such as a telephoniccircuit or a computer network).

The programmer 312 may also be coupled via a communication link 318 to anetwork 320 such as the Internet. This allows any information uploadedfrom the implantable neurostimulator device 110, as well as any programcode or other information to be downloaded to the implantableneurostimulator device 110, to be stored in a database 322 at one ormore data repository locations (which may include various servers andnetwork-connected programmers like the programmer 312). This would allowa patient (and the patient's physician) to have access to importantdata, including past treatment information and software updates,essentially anywhere in the world where there is a programmer (like theprogrammer 312) and a network connection. Alternatively, the programmer312 may be connected to the database 322 over a trans-telephonic link.

In yet another alternative embodiment of the invention, the wirelesslink 310 from the implantable neurostimulator 110 may enable a transferof data from the neurostimulator 110 to the database 322 without anyinvolvement by the programmer 312. In this embodiment, as with others,the wireless link 310 may be established by a short-distance first linkbetween the implantable neurostimulator 110 and a transceiver, with thetransceiver enabled to relay communications over long distances to thedatabase 322, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such astrans-telephonically over a telephonic circuit, or over a computernetwork).

In the disclosed embodiment, the implantable neurostimulator 110 is alsoadapted to receive communications from an interlace device 324,typically controlled by the patient or a caregiver. Accordingly, patientinput 326 from the interface device 324 is transmitted over a wirelesslink to the implantable neurostimulator device 110: such patient input326 may be used to cause the implantable neurostimulator device 110 toswitch modes (on to off and vice versa, for example) or perform anaction (e.g., store a record of EEG data). Preferably, the interfacedevice 324 is able to communicate with the implantable neurostimulator110 through the communication subsystem 430 (FIG. 4), and possibly inthe same manner the programmer 312 does. The link may be unidirectional(as with a magnet and GMR sensor as described below), allowing commandsto be passed in a single direction from the interface device 324 to theimplantable neurostimulator 110, but in an alternative embodiment of theinvention is bidirectional, allowing status and data to be passed backto the interface device 324. Accordingly, the interface device 324 maybe a programmable PDA or other hand-held computing device, such as aPalm Pilot® or PocketPC®. However, a simple form of interface device 324may take the form of a permanent magnet, if the communication subsystem430 is adapted to identify magnetic field and interruptions therein ascommunication signals.

In various embodiments of the invention, the interface device 324 mayalso include additional functions. In one embodiment, the interfacedevice 324 may include an alert capability, enabling the neurostimulatordevice 110 to transmit an alert to the interface device 324 to provide awarning or other information to the patient. The interface device 324may also include therapy functions, including but not limited totranscranial magnetic stimulation (TMS) capabilities. Such therapyfunctions may be controlled by the neurostimulator device 110, theinterface device 324 itself, or some other device on the network.

The implantable neurostimulator device 110 (FIG. 1) generally interactswith the programmer 312 (FIG. 3) as described below. Data stored in thememory subsystem 526 (FIG. 5) can be retrieved by the patient'sphysician through the wireless communication link 310, which operatesthrough the communication subsystem 430 of the implantableneurostimulator 110. In connection with the invention, a softwareoperating program run by the programmer 312 allows the physician to readout a history of neurological events detected including EEG informationbefore, during, and after each neurological event, as well as specificinformation relating to the detection of each neurological event. Theprogrammer 312 also allows the physician to specify or alter anyprogrammable parameters of the implantable neurostimulator 110. Thesoftware operating program also includes tools for the analysis andprocessing of recorded EEG records to assist the physician in developingoptimized seizure detection parameters for each specific patient.

In an embodiment of the invention, the programmer 312 is primarily acommercially available PC, laptop computer, or workstation having a CPU,keyboard, mouse and display, and running a standard operating systemsuch as Microsoft Windows®, Lunix®, Unix®, or Apple Mac OS®. It is alsoenvisioned that a dedicated programmer apparatus with a custom softwarepackage (which may not use a standard operating system) could bedeveloped.

When running the computer workstation software operating program, theprogrammer 312 can process, store, play back and display on the displaythe patient's EEG signals, as previously stored by the implantableneurostimulator 110 of the implantable neurostimulator device.

The computer workstation software operating program also has thecapability to simulate the detection and anticipation of epileptiformactivity. Furthermore, the software operating program of the presentinvention has the capability to allow a clinician to create or modify apatient-specific collection of information comprising, in oneembodiment, algorithms, and algorithm parameters for epileptiformactivity detection. The patient-specific collection of detectionalgorithms and parameters used for neurological activity detectionaccording to the invention will be referred to herein as a detectiontemplate or patient-specific template, in conjunction with otherinformation and parameters generally transferred from the programmer tothe implanted device (such as stimulation parameters, time schedules,and other patient-specific information), make up a set of operationalparameters for the neurostimulator. In the disclosed embodiment of theinvention, the patient-specific template includes information about theparameters needed to identify clusters of events, as will be describedin further detail below.

Following the development of a patient-specific template on theprogrammer 312, the patient-specific template would be downloadedthrough the communications link 310 from the programmer 312 to theimplantable neurostimulator 110.

The patient-specific template is used by the detection subsystem 522 andthe CPU 528 (FIG. 5) of the implantable neurostimulator 110 to detectepileptiform activity in the patient's EEG signals, which can beprogrammed by a clinician to result in responsive stimulation of thepatient's brain, as well as the storage of EEG records before and afterthe detection, facilitating later clinician review.

Preferably, the database 322 is adapted to communicate over the network320 with multiple programmers, including the programmer 312 andadditional programmers 328, 330, and 332. It is contemplated thatprogrammers will be located at various medical facilities andphysicians' offices at widely distributed locations. Accordingly, ifmore than one programmer has been used to upload EEG records from apatient's implantable neurostimulator 110, the EEG records will beaggregated via the database 322 and available thereafter to any of theprogrammers connected to the network 320, including the programmer 312.

FIG. 4 depicts a schematic block diagram of a neurostimulator systemaccording to the invention, including an embodiment of the implantableneurostimulator device 110 comprising a small self-contained externallyprogrammable and controlled neurostimulator that is intracraniallyimplanted.

FIG. 4 is an overall block diagram of the implantable neurostimulatordevice 110 used to modulate cerebral blood flow according to theinvention. Inside the housing of the neurostimulator device 110 areseveral subsystems making up the device. The implantable neurostimulatordevice 110 is capable of being coupled to a plurality of outputs 412,414, 416, and 418 for various types of stimulation as described herein.In the illustrated embodiment, the coupling is accomplished through alead connector.

The outputs 412-418, each of which may be configured to provideelectrical, magnetic, chemical, thermal, or other types of stimulation,are in contact with the patient's brain or are otherwise advantageouslylocated near locations of interest in the patient's brain, whereperfusion is desired to be modulated, or from which other areas of thebrain may be modulated. Each of the outputs 412-418 is electricallycoupled to an output interface 420.

The therapy subsystem 424, which is coupled to the output interface 420,is capable of applying electrical and various other types of stimulationto neurological tissue through the outputs 412-418. This can beaccomplished in any of a number of different manners. For example, withelectrical stimulation, it may be advantageous in some circumstances toprovide stimulation in the form of a substantially continuous stream ofpulses, or on a scheduled basis. It is contemplated that the parametersof the stimulation signal (e.g., frequency, duration, waveform) providedby the therapy subsystem 424 would be specified by other subsystems inthe Implantable device 110, and may be received from external equipmentsuch as the programmer 312, as will be described in further detailbelow.

In accordance with the invention, the therapy subsystem 424 may alsoprovide for other types of stimulation, besides electrical stimulationdescribed above. In particular, in certain circumstances, it may beadvantageous to provide audio, visual, or tactile signals to thepatient, to provide somatosensory electrical stimulation to locationsother than the brain, or to deliver a drug or other therapeutic agent(either alone or in conjunction with stimulation).

Also in the implantable neurostimulator device 110 is a CPU 428, whichcan take the form of a microcontroller. The CPU 428 is capable ofcoordinating the actions of the device 110 and providing differenttherapies on different schedules (and at different locations) to theoutputs 412-418 via the output interface 420, all according toprogramming and commands received from the programmer 312 and thepatient interface device 324 (FIG. 3).

Also provided in the implantable neurostimulator device 110, and coupledto the CPU 428 is a communication subsystem 430. The communicationsubsystem 430 enables communication between the device 110 and theoutside world, particularly the external programmer 312 and patientinterface device 324, both of which are described above with referenceto FIG. 3, and are used with the disclosed embodiment to command andprogram the device 110. As set forth above, the disclosed embodiment ofthe communication subsystem 430 includes a telemetry coil (which may besituated outside of the housing of the implantable neurostimulatordevice 110) enabling transmission and reception of signals, to or froman external apparatus, via inductive coupling. Alternative embodimentsof the communication subsystem 430 could use an antenna for an RF linkor an audio transducer for an audio link. Preferably, the communicationsubsystem 430 also includes a GMR (giant magnetoresistive effect) sensorto enable receiving simple signals (namely the placement and removal ofa magnet) from a patient interface device; this capability can be usedto initiate EEG recording as will be described in further detail below.

If the therapy subsystem 424 includes the audio capability set forthabove, it may be advantageous for the communication subsystem 430 tocause the audio signal to be generated by the therapy subsystem 424 uponreceipt of an appropriate indication from the patient interface device(e.g., the magnet used to communicate with the GMR sensor of thecommunication subsystem 430), thereby confirming to the patient orcaregiver that a desired action will be performed, e.g. that an EEGrecord will be stored.

Rounding out the subsystems in the implantable neurostimulator device110 are a power supply 432 and a clock supply 434. The power supply 432supplies the voltages and currents necessary for each of the othersubsystems. The clock supply 434 supplies substantially-all of the othersubsystems with any clock and timing signals necessary for theiroperation, including a real-time clock signal to coordinate programmedand scheduled actions.

As described above, the described embodiment is adapted to be used in animplanted environment to modulate a patient's cerebral blood flow forthe control of epilepsy or other neurological disorders.

FIG. 5 depicts a schematic block diagram of an implantable responsiveneurostimulator system according to the invention. The embodimentillustrated in FIG. 5 includes the capabilities of the programmableneurostimulator described with reference to FIG. 4, and is capable ofacting responsively as set forth below. As the term is used herein, aresponsive neurostimulator is a device capable of detecting undesiredactivity (or other neurological events) and providing electricalstimulation to neural tissue in response to that activity, where theelectrical stimulation is specifically intended to terminate theundesired activity, treat a neurological event, prevent an unwantedneurological event from occurring, or lessen the severity or frequencyof certain symptoms of a neurological disorder.

It should be recognized that the embodiment of the device described andillustrated herein is preferably a responsive neurostimulator fordetecting and treating epilepsy by detecting seizure precursors andpreventing and/or terminating epileptic seizures. It will be recognized,and it is described elsewhere herein, that similar methods and devicesmay be used to treat other neurological disorders as well.

FIG. 5 is an overall block diagram of the implantable neurostimulatordevice 110 used for measurement, detection, and treatment according tothe invention. Inside the housing of the neurostimulator device 110 areseveral subsystems making up the device. The implantable neurostimulatordevice 110 is capable of being coupled to a plurality of probes 512,514, 516, and 518 (each of which may be individually or togetherconnected to the implantable neurostimulator device 110 via one or moreleads) for sensing and stimulation. In the illustrated embodiment, thecoupling is accomplished through a lead connector. Although four probesare shown in FIG. 5, it should be recognized that any number ispossible, and in the embodiment described in detail herein, eightelectrodes on two leads are used. In fact, it is possible to employ anembodiment of the invention that uses a single lead with at least twoelectrodes, or two leads each with at least a single electrode (or witha second electrode provided by a conductive exterior portion of thehousing in one embodiment), although bipolar sensing between two closelyspaced electrodes on a lead is preferred to minimize common mode signalsincluding noise.

The probes (as disclosed, electrodes) 512-518 are in contact with thepatient's brain or are otherwise advantageously located to receivesignals or provide electrical stimulation. Each of the electrodes512-518 is also electrically coupled to a probe interface 520.Preferably, the probe interface is capable of selecting each electrode(or other sensor or probe) as required for sensing and stimulation;accordingly the probe interface is coupled to a detection subsystem 522and a stimulation subsystem 524 (which, in an embodiment of theinvention, may provide therapy and have outputs other than electricalstimulation, as described below). The electrode interface may alsoprovide any other features, capabilities, or aspects, including but notlimited to amplification, isolation, and charge-balancing functions,that are required for a proper interface with neurological tissue andnot provided by any other subsystem of the device 110.

The detection subsystem 522 includes and serves primarily as a cerebralblood flow and EEG waveform analyzer; detection is accomplished inconjunction with a central processing unit (CPU) 528. The analysisfunctions are adapted to receive signals from the probes 512-518,through the probe interface 520, and to process those signals toidentify neurological activity indicative of a seizure or a precursor toa seizure. One way to implement EEG analysis functionality is disclosedin detail in U.S. Pat. No. 6,016,449 to Fischell et al., incorporated byreference above. Additional inventive methods are described in U.S. Pat.No. 6,810,285 to Pless et al. entitled “SEIZURE SENSING AND DETECTIONUSING AN IMPLANTABLE DEVICE,” of which details will be set forth below(and which is also hereby incorporated by reference as though set forthin full). The detection subsystem may optionally also contain furthersensing and detection capabilities, including but not limited toparameters derived from other physiological conditions (such aselectrophysiological parameters, temperature, blood pressure, etc.). Ingeneral, prior to analysis, the detection subsystem performsamplification, analog to digital conversion, and multiplexing functionson the signals in the sensing channels received from the probes 512-518.

The therapy subsystem 524 is capable of applying electrical and othertypes of stimulation to neurological tissue through the probes 512-518,to the extent such probes are capable of applying stimulation. This canbe accomplished in any of a number of different manners. For example, itmay be advantageous in some circumstances to provide electrical or otherstimulation in the form of a substantially continuous stream of pulses,or on a scheduled basis. Preferably, therapeutic stimulation is providedin response to abnormal neurological events detected by the EEG analyzerfunction of the detection subsystem 422 and to modulate cerebral bloodflow as described herein. As illustrated in FIG. 5, the therapysubsystem 524 and the analysis functions of the detection subsystem 522are in communication: this facilitates the ability of the therapysubsystem 524 to provide responsive stimulation as well as an ability ofthe detection subsystem 522 to blank the amplifiers while electricalstimulation is being performed to minimize stimulation artifacts. It iscontemplated that the parameters of the stimulation signal (e.g.,frequency, duration, waveform) provided by the therapy subsystem 524would be specified by other subsystems in the implantable device 110, aswill be described in further detail below.

In accordance with the invention, the therapy subsystem 524 may alsoprovide for other types of stimulation, besides electrical stimulationdescribed above. Such stimulation may be provided through the probes512-518, or alternative therapy outputs may be provided, such as athermal stimulator 536, a drug dispenser 538, or a transducer 540, whichmay be adapted for placement in, on, or near the brain, or elsewhere. Inparticular, in certain circumstances, it may be advantageous to provideaudio, visual, or tactile signals to the patient, to providesomatosensory electrical stimulation to locations other than the brain,or to deliver a drug or other therapeutic agent (either alone or inconjunction with stimulation).

Also in the implantable neurostimulator device 110 is a memory subsystem526 and the CPU 528, which can take the form of a microcontroller. Thememory subsystem is coupled to the detection subsystem 522 (e.g., forreceiving and storing data representative of sensed EEG signals andevoked responses), the therapy subsystem 524 (e.g. for providingstimulation waveform parameters to the therapy subsystem), and the CPU52S, which can control the operation of (and store and retrieve datafrom) the memory subsystem 520. In addition to the memory subsystem 526,the CPU 528 is also connected to the detection subsystem 522 and thetherapy subsystem 524 for direct control of those subsystems.

Also provided in the implantable neurostimulator device 110, and coupledto the memory subsystem 526 and the CPU 528, is a communicationsubsystem 530. The communication subsystem 530 enables communicationbetween the device 110 and the outside world, particularly the externalprogrammer 312 and patient interface device 324, both of which aredescribed above with reference to FIG. 3. As set forth above, thedisclosed embodiment of the communication subsystem 530 includes atelemetry coil (which may be situated outside of the housing of theimplantable neurostimulator device 110) enabling transmission andreception of signals, to or from an external apparatus, via inductivecoupling. Alternative embodiments of the communication subsystem 530could use an antenna for an RF link or an audio transducer for an audiolink. Preferably, the communication subsystem 530 also includes a GMR(giant magnetoresistive effect) sensor to enable receiving simplesignals (namely the placement and removal of a magnet) from a patientinterface device; this capability can be used to initiate EEG recordingas will be described in further detail below.

If the therapy subsystem 524 includes the audio capability set forthabove (e.g., via the transducer 540), it may be advantageous for thecommunication subsystem 530 to cause the audio signal to be generated bythe therapy subsystem 524 upon receipt of an appropriate indication fromthe patient interface device (e.g. the magnet used to communicate withthe GMR sensor of the communication subsystem 530), thereby confirmingto the patient or caregiver that a desired action will be performed,e.g. that an EEG record will be stored.

Rounding out the subsystems in the implantable neurostimulator device110 are a power supply 532 and a clock supply 534. The power supply 532supplies the voltages and currents necessary for each of the othersubsystems. The clock supply 534 supplies substantially all of the othersubsystems with any clock and timing signals necessary for theiroperation, including a real-time clock signal to coordinate programmedand scheduled actions and the timer functionality used by the detectionsubsystem 522 that is described in detail below.

It should be observed that while the memory subsystem 526 is illustratedin FIG. 5 as a separate functional subsystem, the other subsystems mayalso require various amounts of memory to perform the functionsdescribed above and others. Furthermore, while the implantableneurostimulator device 110 is preferably a single physical unit (i.e. acontrol module) contained within a single implantable physicalenclosure, namely the housing described above, other embodiments of theinvention might be configured differently. The neurostimulator 110 maybe provided as an external unit not adapted for implantation, or it maycomprise a plurality of spatially separate units each performing asubset of the capabilities described above, some or all of which mightbe external devices not suitable for implantation. Also, it should benoted that the various functions and capabilities of the subsystemsdescribed above may be performed by electronic hardware, computersoftware (or firmware), or a combination thereof. The division of workbetween the CPU 528 and the other functional subsystems may alsovary—the functional distinctions illustrated in FIG. 5 may not reflectthe partitioning and integration of functions in a real-world system ormethod according to the invention.

FIG. 6 illustrates details of the detection subsystem 522 (FIG. 5).Inputs from the probes 512-518 are on the left, and connections to othersubsystems are on the right.

Signals received from the electrodes 512-518 (as routed through theprobe interface 520) are received in an input selector 610. The inputselector 610 allows the device to select which probes (of the probes512-518) should be routed to which individual sensing channels of thedetection subsystem 522, based on commands received through a controlinterface 618 from the memory subsystem 526 or the CPU 528 (FIG. 5).Preferably, for electrographic and impedance measurements, each sensingchannel of the detection subsystem 522 receives a bipolar signalrepresentative of the difference in electrical potential between twoselectable electrodes. Accordingly, the electrode selector 610 providessignals corresponding to each pair of selected electrodes (of the probes512-518) to a sensing front end 612, which performs amplification,analog to digital conversion, and multiplexing functions on the signalsin the sensing channels.

A multiplexed input signal representative of all active sensing channelsis then fed from the sensing front end 612 to a waveform analyzer 614.The waveform analyzer 614 is preferably a special-purpose digital signalprocessor (DSP) adapted for use with the invention, or in an alternativeembodiment, may comprise a programmable general-purpose DSP. In thedisclosed embodiment, the waveform analyzer has its own scratchpadmemory area 616 used for local storage of data and program variableswhen the signal processing is being performed. In either ease, thesignal processor performs suitable measurement and detection methodsdescribed generally above and in greater detail below. Any results fromsuch methods, as well as any digitized signals intended for storagetransmission to external equipment, are passed to various othersubsystems of the neurostimulator device 110, including the memorysubsystem 526 and the CPU 528 (FIG. 5) through a data interface 620.Similarly, the control interface 618 allows the waveform analyzer 614and the input selector 610 to be in communication with the CPU 528.

FIG. 7 illustrates the components functionally present in an exemplarytherapy-subsystem 524 according to the invention. Through an outputselector 710, the therapy subsystem 524 is capable of driving a numberof outputs, including the thermal stimulator 536, the drug dispenser538, and the audio transducer 540 illustrated in FIG. 5. Other outputsinclude leads for electrical stimulation and other stimulators asdescribed in greater detail below with reference to FIGS. 8-11 and 13.Preferably, the output selector 710 is configured and may be programmedto drive more than one output, either in sequence or simultaneously.

The nature of the outputs is defined by a signal generator 712,advantageously designed to be able to produce different types of outputsignals for different types of outputs. For example, for electricalstimulation, biphasic pulsatile stimulation or low-frequency sine wavestimulation may be advantageous signals to generate, whereas for a burstof thermal stimulation, a single-polarity longer-duration pulse may bemore appropriate. For various forms of active sensing described indetail below (in which a physiological or other physical response to anapplied stimulus is measured), signals generated by the signal generator712 are preferably coordinated with measurements made by the detectionsubsystem 522 (FIG. 5).

Such coordination and control of the signal generator 712 isaccomplished through a therapy controller 714, which may include memory716 to “play back” therapy waveforms and for other purposes suchwaveforms may also be received via a data interface 720 from the mainmemory subsystem 526 or the CPU 528. The therapy controller receivesinput from a control interface 718, which is coupled to the CPU 528,thereby allowing the CPU 528 to control both the therapy subsystem 524and the detection subsystem 522. Through the control interface 718, theCPU 528 is also capable of controlling the application of therapy (orother stimulation) to a desired combination of outputs via the outputselector 710.

FIGS. 8-13 illustrate several embodiments of probes advantageouslyusable in a system according to the invention to measure and modulateperfusion. The chronically implantable probes illustrated in FIGS. 8-13are advantageously connected to a device 110 according to the invention,and in the illustrated embodiments, have distal ends generally 0.5-3 mmin diameter, are at least partially flexible, and are of a lengthsufficient to reach from the device 110 to a desired target. Theillustrations are schematic in nature and are not to scale. The probesof FIGS. 8-13 are illustrated as generally cylindrical depth probes,capable of being positioned within the gray or white matter of apatient's brain, but it should be recognized that surface corticalprobes are also advantageous in certain embodiments: the differencesbetween the illustrated probes and their cortical counterparts would beknown to a practitioner of ordinary skill, and would primarily entail adifferent (paddle-shaped) physical configuration at the distal end.

Referring now to FIG. 8, an optical probe 810 capable of measuringcerebral perfusion and applying optical stimulation is illustrated. Theprobe 810 includes an optically translucent distal tip 812 and opaquebarrier 814 separating a light source 816 (typically one or more lightemitting diodes, or LEDs) and a light sensor 818 (typically aphotodiode, but it may also include a CCD or other light sensor). In theillustrated embodiment, the light source 816 and light sensor 818 areconnected to a buffer 820, which in turn is coupled to the device 110.This configuration allows a single set of control wires (typically apair) to both send information bi-directionally between the probe 810and the device 110. In an alternative embodiment, the buffer 820 may beomitted and multiple control links may be established between the device110 and the light source 816 and sensor 818: in this embodiment theprobe interface 520 (FIG. 5) would perform the buffering functionsotherwise provided by the buffer 820.

The optical probe 810 of FIG. 8 is advantageously used to measureperfusion via pulse oximetry methods. The disclosed embodiment isconfigured to measure reflected light; embodiments measuringtransmissivity are also possible. The light source 816 includes twoLEDs, one red LED in the 600-750 nm range and an infrared LED in the850-1000 nm range. To obtain a single measurement, the two LEDs arepulsed (preferably in sequence) and two corresponding measurements areobtained at the light sensor 818, a photodiode. The ratio of redreflectivity to infrared reflectivity is calculated (by the detectionsubsystem 522 or CPU 528). Preferably, multiple ratio measurements areobtained over the course of at least one heart beat to obtain a valuefor peak perfusion, typically by subtracting minimum values (baselines)from maximum values (maximum perfusion). The peak value is compared to apreprogrammed lookup table to obtain an oxygen saturation value; thecontents of the lookup table would be routine to calculate for apractitioner of ordinary skill.

It will be noted that perfusion measurements obtained by the opticalprobe 810 are typically relevant only in comparison to previouslyobtained values or trends, as measurements may be affected over a longterm by tissue growth and other physiological changes around the probe810. As will be described in detail below, systems and methods accordingto the invention perform accordingly.

In an embodiment of the invention, the light source 816 is furtheroperable to optically stimulate brain tissue, which may result inperfusion changes or other desired neurophysiological results. Forpurposes of measurement, however, it is preferable to operate the lightsource 816 with low amplitude, duration, and other characteristics thatare unlikely to cause undesired effects.

A thermal probe 910 is illustrated in FIG. 9; it is capable of measuringcerebral perfusion by thermographic means. The thermal probe 910includes a thermally conductive distal tip 912 (the shape of which is asdesired to reach a preferred target or region) coupled to a thermalenergy source 914 (such as a Peltier junction or stack) and atemperature sensor 916 (in one embodiment, a temperature sensitiveresistor). The thermal probe 910 is otherwise relatively thermallyinsulated. As shown, the thermal energy source 914 and the temperaturesensor 916 are electrically coupled to a switch 918 facilitating the useof a single set of control wires, and as with the optical probe 810, theswitch 918 may be omitted in favor of multiple connections. The switch918 need not be as complex as the buffer 820 (FIG. 8), as thermographycalls for temperature measurements to be obtained after thermalstimulation is applied; simultaneous operation of the thermal energysource 914 and the temperature sensor 916 is generally not required. Theswitch is advantageously operated via signals from the device 110.

Thermographic measurement of perfusion is generally accomplished byapplying a caloric stimulus (via the thermal energy source 914), eitherhot or cold, and measuring the temperature over an interval thereafterto determine how quickly heat dissipates. Increased dissipationcorrelates with higher blood flow. Thermographic techniques, and theircalibration, are well known to practitioners of ordinary skill. As withoptical measurements, thermographic measurements of perfusion are mostuseful in a relative sense, compared to a previously measured baseline,and may be subject to long-term changes.

Thermal stimulation may also be performed by the probe 910 to modulatecerebral perfusion; generally, and increase in temperature will tend toincrease blood flow in the region, and a decrease in temperature willlead to lower blood flow. Preferably, when measurements are to be made,smaller perturbances to temperature are preferred.

Thermographic probes as generally described herein are commerciallyavailable.

FIG. 10 illustrates an ultrasonic probe 1010, including an ultrasonictransmitter 1012, an ultrasonic receiver 1014, and a processor 1016 allbehind a partially acoustically transparent distal probe tip 1018. Inthe disclosed embodiment, the ultrasonic probe 1010 is adapted tomeasure perfusion via Doppler flowmetry, a technique well known in theare. The disclosed embodiment includes the Doppler processing in theprobe via the processor 1016, though the calculations may also beperformed on board the device 110.

The ultrasonic transmitter 1012 is, in the disclosed embodiment, apiezoelectric transducer configured to operate at a frequency greaterthan approximately 1 MHz. The ultrasonic receiver 1014 is adapted toreceive at a range of similar and compatible frequencies. Pulsedmeasurements enable selection of measurement depth (e.g., the distancein front of the probe 1010 from which a measurement is taken).

Ultrasonic stimulation may also be performed by an ultrasonic probe 1010according to the invention; ultrasonic stimulation generally operates toincrease perfusion at the stimulation site.

Ultrasonic flow probes potentially suitable for use in connection withvarious embodiments of the present invention are commercially available.Regardless of the embodiment, when placing an ultrasonic probe, it isparticularly important to avoid air bubbles and other gas pockets infront of the transducer, as such obstructions may confound measurements.

FIG. 11 illustrates an electromagnetic probe 1110 according to theinvention, which includes a first field generating coil 1112 and asecond sensing coil 1114 behind a magnetically permeable tip 1116. Aswith the other probe embodiments, a buffer 1118 is provided to enable asingle set of control wires to be used and to offload some processingfrom the device 110.

The electromagnetic probe 1110 is capable of measuring blood flow volumeand rate by applying a magnetic field with the first field generatingcoil 1112 and measuring changes in electrical potential created acrossthe second sensing coil 1114 caused by the movement of ferromagnetic orpolarized objects, in the present case blood cells, within the field.The general technique of electromagnetic flowmetry is well known.

Localized electromagnetic stimulation may also be applied by theelectromagnetic probe 1110. Depolarization potentially caused by amagnetic field may have therapeutic effects at or near a seizure focusor at a functionally relevant brain structure, or the magnetic field maybe manipulated to affect perfusion in a desired manner according to theinvention. In an embodiment of the invention, transcranial magneticstimulation may be applied at a global scale (e.g., through theinterface device 324, FIG. 3) to accomplish similar results.

FIG. 12 illustrates an electrochemical oxygen probe 1210, which includesan oxygen sensor 1212 disposed behind a permeable tip 1214 or membrane.There are three common types of dissolved oxygen sensing probes:polarographic sensors, galvanic sensors, and optical fluorescencesensors, any of which may be adapted to serve the purposes of theinvention to the extent they are biocompatible for long-term implantpurposes. Dissolved oxygen levels correlate positively with perfusionlevels, and may be used by systems and methods according to theinvention to measure blood flow. The disclosed oxygen probe 1210 is notadapted to perform stimulation.

Other types of electrochemical sensing probes may also be used in thisapplication, such as those detecting the presence of lactate in theneural tissue. These chemical markers may also be indicators of abnormalmetabolism and perfusion levels.

A lead 1310 with four ring electrodes 1312 is illustrated in FIG. 13. Inaddition to traditional electrographic sensing and electricalstimulation as described above, the lead 1310 can be used to measurelocal perfusion by electrical impedance plethysmography. Accordingly,low current and short pulses of electrical stimulation (to avoidundesired depolarization and electrographic interference artifacts, andto improve battery life) are applied and impedance is measured between apair of electrodes 1312 on the lead 13 in.

As with other measurements described herein, electrical impedanceplethysmography is advantageously used in a relative comparison tobaseline measurements, rather than as an absolute value, further,compensation for routine heart-rhythm-based variations (by takingaverage or peak values over several measurements) is also deemedadvantageous.

With a sufficient number of electrodes disposed around a target site, itis possible to use a series of impedance measurements between differentsets of electrodes to reconstruct a tomographic image of blood flow;techniques for accomplishing electrical impedance tomography are wellknown. In a presently preferred embodiment of the invention, data iscollected for tomographic measurements by the device 110 and transferredto the programmer 312 or other external apparatus, where the intensivecomputations needed to reconstruct visualizations are more feasiblyearned out.

FIG. 14 illustrates a sample hypothetical graph of cerebral perfusionmeasurements. At its start 1412, a perfusion curve 1410 (not illustratedto any particular scale) is approximately centered between an upperthreshold 1414 and a lower threshold 1416. The perfusion curve 1410shows gradually increasing perfusion up to a first time 1418, at whichthe thresholds 1414 and 1416 are recalculated to accommodate long-termtrending. The thresholds 1414 and 1416 are recalculated again at asecond time 1420, and shortly thereafter at a third time 1422 the curve1410 starts to drop below the lower threshold 1416. This drop below anadjusted threshold indicates, in an exemplary system or method accordingto the invention, an undesired drop in perfusion, indicating that atherapeutic action should be taken as discussed in connection with theflow chart of FIG. 15 below. In an embodiment of the invention, cerebralblood flow is directly modulated (by means described herein) to increaseit above the threshold 1416, or other actions may be taken alone or inconjunction with blood flow modulation.

(During the time period 1422 the curve 1410 is below the lower threshold1416, the thresholds 1414 and 1416 are not recalculated. Thresholds arereadjusted periodically (in a preferred embodiment of the device 110, aselectable number of seconds).

A method according to the invention is performed, as illustrated in FIG.15, by initializing a perfusion trend value (step 1510). This isperformed by performing an initial perfusion measurement (or average ofa sequence of measurements) and storing it in a trend variable.

Perfusion at a desired site is then measured (step 1512) by one of themethods described herein or any other applicable technique. Themeasurement is then compared (step 1514) to the previously calculatedtrend. If the perfusion measurement exceeds an upper bound (step 1516),namely the trend value plus an upper threshold value (or in analternative embodiment, the trend value multiplied by an upper thresholdfactor generally greater than one), then a first action is performed(step 1518). This condition, when the perfusion exceeds a threshold,indicates hyperperfusion that may be an undesired or pathologicalcondition, or at least an indication that conditions are out ofequilibrium and require therapeutic intervention.

To treat hyperperfusion, electrical (or other) stimulation according tothe invention may be applied to the patient's caudate nucleus;stimulating other anatomical targets may also serve to decreaseperfusion. An audio alert, somatosensory stimulation, or otherindication may also be provided to the patient or a caregiver via thedevice 110 or its communication subsystem 530 (FIG. 5).

If the perfusion measurement exceeds (i.e., is lower than) a lower bound(step 1520), namely the trend value minus a lower threshold value (or inan alternative embodiment, the trend value multiplied by a lowerthreshold factor generally less than one), then a second action isperformed (step 1522). This condition, when the perfusion is lower thana threshold, indicates hypoperfusion that may be an undesired orpathological condition suggestive of an imminent epileptic seizure.Hypoperfusion may be treated by applying electrical (or other)stimulation at or near the site where the hypoperfusion was observed,frequently a seizure focus. As with hyperperfusion, feedback may beprovided to the patient or caregiver. Alternatively, external therapy(such as transcranial magnetic stimulation) may be applied, eitherautomatically or manually (based on an indication).

As set forth above, for either hyperperfusion or hypoperfusion,stimulation of a variety of anatomical targets may be performedaccording to the invention to produce beneficial changes in corticalblood flow to treat neurological disorders. Specifically, but not by wayof limitation, potential stimulation targets include cortex of the brain(including specialized structures such as the hippocampus), whitematter, basal ganglia (including the caudate nucleus), the brain stem,the spinal cord, the cerebellum or any of various cranial or peripheralnerves including the vagus nerve. Somatosensory stimulation (includingsound, vision, and touch) may be suitable in some circumstances,particularly for acute therapy.

If the perfusion is within bounds, the trend variable is updated (step1524), preferably periodically as described above. The method proceedsby repealing a perfusion measurement (step 1512) and continuing.

The actions taken need not be therapeutic in nature; they may serveother purposes. In one embodiment of the invention, the device 110 isessentially a seizure counter adapted to identify and collectinformation about periods of abnormal perfusion for later retrieval.

The flow chart of FIG. 15 is not an exclusive description of methodsperformed by a system according to the invention. Rather, it describes asingle aspect of a single embodiment of a system according to theinvention for observing blood flow and taking action in response tochanges. This method may be performed in conjunction with, or inparallel with, other methods generally performed by implantable devicesand implantable neurostimulators specifically. In particular, cerebralblood flow management may be considered a useful adjunctive therapy foran implanted responsive neurostimulator such as that described in detailin U.S. Pat. No. 6,810,285, referenced above, that is also capable ofapplying pulsatile electrical stimulation in response to detectedabnormal electrographic activity.

One possible clinical scenario is as follows. Consider a patient inwhich hypo-perfusion is exhibited on one side of the brain where thepatient's epileptiform activity originates. In the contralateral side,perfusion may be normal. This is considered to be a likely scenario,though by no means the only possible scenario. Some time before anepileptic seizure is likely to occur, perfusion starts to rise in theepileptic hemisphere, and plunges abruptly in the contralateralhemisphere just prior to the seizure. In this scenario, two parallelcourses of the flow illustrated in FIG. 15 are contemplated, each onemeasuring perfusion in an area of interest in opposite hemispheres.

Interictally, while perfusion is low in the epileptic (hypo-perfused)hemisphere, a System according to the invention is programmed to deliverelectrical stimulation to increase perfusion and normalize the system.Each burst of stimulation tends to have a short-term effect. Stimulationmay be provided intermittently but regularly, while perfusion ismonitored. If perfusion rises beyond the amount caused by the interictalstimulation, and especially if it is accompanied by a drop in perfusionin the contralateral hemisphere, then seizure activity may beanticipated. Accordingly, the stimulation strategy is altered in lightof the changed brain state, and an alternative course of therapy isinitiated, which may include some or all of the following. (1)stimulation of the caudate nucleus to decrease excitability in theepileptic hemisphere; (2) stimulation of the contralateral cortex toincrease perfusion there; and (3) therapeutic electrical stimulation toreduce the likelihood of seizure activity. If ictal electrographicactivity is then also observed in a system according to the invention,further actions may also be taken. Different actions may also be takendepending on whether the patient is asleep or awake (as potentiallyindicated by electrographic activity) or based on other measures oflevel of arousal or activity, as these factors may also tend to affectperfusion.

It should be observed that while the foregoing detailed description ofvarious embodiments of the present invention is set forth in somedetail, the invention is not limited to those details and an implantablemedical device or system made according to the invention can differ fromthe disclosed embodiments in numerous ways. In particular, it will beappreciated that embodiments of the present invention may be employed inmany different applications to responsively treat epilepsy and otherneurological disorders. It will be appreciated that the functionsdisclosed herein as being performed by hardware and software,respectively, may be performed differently in an alternative embodiment.It should be further noted that functional distinctions are made abovefor purposes of explanation and clarity; structural distinctions in asystem or method according to the invention may not be drawn along thesame boundaries. Hence, the appropriate scope hereof is deemed to be inaccordance with the claims as set forth below.

1. An implantable device for responding to a neurological disorder in ahuman patient, the device comprising: a detection subsystem coupled toat least one sensor, wherein the sensor generates a signalrepresentative of a cerebral perfusion measurement, and wherein thedetection subsystem is operative to receive and process the signal; anda processor operative to identify a condition in the signal.
 2. Theimplantable device of claim 1, wherein the neurological disorder isepilepsy.
 3. The implantable device of claim 1, wherein the condition isrepresentative of a symptom of the neurological disorder.
 4. Theimplantable device of claim 1, wherein the signal indicates the onset ofan epileptic seizure.
 5. The implantable device of claim 1, wherein thesignal represents a precursor anticipating an epileptic seizure.
 6. Theimplantable device of claim 1, wherein the condition comprises a changein the cerebral perfusion measurement.
 7. The implantable device ofclaim 1, further comprising a therapy subsystem coupled to at least onetherapy output, wherein the therapy subsystem is operative toselectively initiate delivery to the therapy output.
 8. The implantablemedical device of claim 7, wherein the processor is programmed to causethe therapy subsystem to initiate application of the therapy in responseto the identified condition.
 9. The implantable medical device of claim7, wherein the therapy subsystem is adapted to modulate cerebralperfusion.
 10. The implantable device of claim 7, wherein the sensorcomprises at least one component from the group consisting of an opticaloximetry measurement component, an electromagnetic field measurementcomponent, a thermographic measurement component, an ultrasonictransducer component, and an electrochemical oxygen concentrationmeasurement component.
 11. The implantable device of claim 7, whereinthe therapy output comprises an ultrasonic transducer.
 12. Theimplantable device of claim 7, wherein the sensor comprises a sensingelectrode.
 13. The implantable device of claim 12, wherein the sensingelectrode is adapted to measure an electrical impedance.
 14. Theimplantable device of claim 12, wherein the sensing electrode is adaptedto measure an electrographic signal.
 15. The implantable device of claim7, wherein the therapy output comprises a stimulation electrode.
 16. Asystem for responding to a neurological disorder in a human patient, thedevice comprising: a control unit comprising a detection subsystemcoupled to at least one sensor, wherein the sensor generates a signalrepresentative of a cerebral perfusion measurement, and wherein thedetection subsystem is operative to receive and process the signal; aprocessor coupled to receive the signal and identify a condition in thesignal.
 17. The system of claim 16, wherein the control unit comprisesan implantable module.
 18. The system of claim 17, wherein the controlunit is adapted to communicate with an external apparatus.
 19. Thesystem of claim 18, wherein the external apparatus includes theprocessor.
 20. The system of claim 18, wherein the control unitcomprises a therapy subsystem coupled to at least one therapy output,and wherein the therapy subsystem is operative to selectively initiatedelivery of a therapy to the therapy output.